| Abstract | Deoksiribonukleinska kiselina (DNA), osnovna molekula naslijeđivanja, svakodnevno trpi oštećenja nastala endogenim i/ili egzogenim putem, koja ako se ne poprave mogu dovesti do mutacija koje pridonose apoptozi stanica, starenju organizma, razvoja neurodegenerativnih bolesti i tumorogeneze. Kako se to ne bi dogodilo, stanice reagiraju pokretanjem odgovora na oštećenje DNA (DDR), koji regrutira mehanizme popravka DNA ovisno o tipu oštećenja. Popravak izrezivanjem baza (BER), popravak iscijecanjem nukleotida (NER) i popravak pogrešno sparenih baza (MMR) popravljaju jednolančane lomove DNA, dok su nehomologno spajanje krajeva DNA (NHEJ) i homologna rekombinacija (HR) zaduženi za popravak dvolančanih lomova DNA. Homologna rekombinacija vrlo je složen proces u kojem glavnu ulogu imaju geni poput BRCA1, BRCA2, PALB2, ATM, ATR, BACH1, BARD1. Nedostatnu homolognu rekombinaciju mogu izazvati mutacije gena povezanih s procesom homologne rekombinacije, ali može nastasti i putem epigenetskih promjena, što može uzrokovati tumore dojke, jajnika, prostate i gušterače, te razvoj bolesti poput Fanconijeve anemije i Bloomovog sindroma. Dijagnostika nedostatne homologne rekombinacije (HRD), izuzetno značajna zbog određivanja optimalne terapijske opcije, zasad nije polučila zadovoljavajuće rezultate. Onkološkim pacijentima, u čijim tumorskim stanicama je detektirana ili somatska ili mutacija zametne loze koja dovodi do nedostatne homologne rekombinacije, danas je poboljšano preživljenje i ishodi liječenja razvojem inhibitora poli (ADP-riboza) polimeraza (PARP) (olaparib, rucaparib, niraparib, talazoparib). Cilj ovog diplomskog rada je dati detaljniji pregled na mehanizme popravka DNA s naglaskom na homolognu rekombinaciju, te prikazati bolesti, a posebice solidne tumore, prouzročene nedostatnom homolognom rekombinacijom, te njihovu dijagnostiku i terapiju. |
| Abstract (english) | Deoxyribonucleic acid (DNA), basic molecule of inheritance, gets damaged on daily basis by endogenous and/or exogenous agents. Damaged DNA, if left unrepaired, can lead to mutations which can cause cell death, organism senescence, neurodegenerative disease and tumorigenesis. In order to stop that, cells initiate DNA damage response (DDR), which recruits DNA repair pathaways depending on the type of DNA damage. Single-stranded DNA breaks can be repaired by base excision repair (BER), nucleotide excision repair (NER) or mismatch repair (MMR), while double-stranded DNA breaks are repaired either by non-homologous end-joining (NHEJ) or homologous recombination (HR) pathaway. Homologous recombination is a highly complex pathaway in which genes such as BRCA1, BRCA2, PALB2, ATM, ATR, BACH1, BARD1 play pivotal role. Homologous recombination deficiency (HRD) can be caused by mutations in genes related to HR pathaway, however it can be also caused by epigenetic changes in given genes, which can contribute to breast, ovary, prostate and pancreas carcinogensis or add to development of Fanconi anemia or Bloom syndrome. HRD diagnostics, extremely significant in terms of selecting optimal therapy, so far has not obtained adequate results. Oncology patients, in whose tumor cells either somatic or germ-line mutation which leads to HRD has been detected, today have better survival rates due to development of PARP inhibitors (olaparib, rucaparib, niraparib, talazoparib). The aim of this gradute thesis is to give a detailed review of DNA repair pathaways with emphasis on homologous recombination, as well as to present diseases, especially solid tumors, caused by HRD and their diagnostics along with therapy options. |
